The spectrum of MAPK-ERK pathway genomic alterations in gynecologic malignancies: Opportunities for novel therapeutic approaches.

To investigate the incidence of MAPK/ERK pathway genomic alterations among patients with gynecologic malignancies. We accessed the American Association of Cancer Research Genomics Evidence of Neoplasia Information Exchange publicly available dataset (v13.0). Patients with malignant tumors of the ovary, uterus, and cervix were identified. Following stratification by tumor site and histology, we examined the prevalence of MAPK/ERK pathway gene alterations (somatic mutation, and/or structural chromosome alterations). We included the following RAS-MAPK pathway genes known to be implicated in the dysregulation of the pathway; KRAS, NRAS, BRAF, HRAS, MAP2K1, RAF1, PTPN11, NF1, and ARAF. Data from the OncoKB database, as provided by cBioPortal, were utilized to determine pathogenic gene alterations. We identified a total of 10,233 patients with gynecologic malignancies; 48.2% (n = 4937) with ovarian, 45.2% (n = 4621) with uterine and 6.6% (n = 675) with cervical cancer respectively. The overall incidence of MAPK pathway gene alterations was 21%; the most commonly altered gene was KRAS (13%), followed by NF1 (7%), NRAS (1.3%), and BRAF (1.2%). The highest incidence was observed among patients with mucinous ovarian (71%), low-grade serous ovarian (48%), endometrioid ovarian (37%), and endometrioid endometrial carcinoma (34%). Approximately 1 in 5 patients with a gynecologic tumor harbor a MAPK/ERK pathway genomic alteration. Novel treatment strategies capitalizing on these alterations are warranted.

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Copyright © 2023. Published by Elsevier Inc.

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Declaration of Competing Interest FS: Scientific Advisory Board for Zentalis Pharmaceuticals, and GSK; grant funding from REPARE Therapeutics. GBM SAB/Consultant: Amphista, Astex, AstraZeneca, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, GSK, ImmunoMET, Infinity, Ionis, Leapfrog Bio, Lilly, Medacorp, Nanostring, Nuvectis, PDX Pharmaceuticals, Qureator, Roche, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals. Stock/Options/Financial: Bluedot, Catena Pharmaceuticals, ImmunoMet, Nuvectis, SignalChem, Tarveda, Turbine. Licensed Technology. HRD assay to Myriad Genetics, DSP patents with Nanostring. Sponsored research. AstraZeneca, GBM is supported by a kind gift from the Miriam and Sheldon Adelson Medical Research Foundation. DN is supported by the Penn Presbyterian George L. and Emily McMichael Harrison Fund for Research in Obstetrics and Gynecology, Kaleidoscope of Hope, Foundation for Women's Cancer Move4Her and Sandy-Rollman grants. MC: Honoraria Verastem. Stock/Options/Financial: Bausch Health Companies, Illumina, aiGENE, DentalToday, Hexamer Therapeutics. SW: Consultant ZielBio, AstraZeneca, Clovis Oncology, Eisai, Merch, Mereo, Mersana, SeaGen, Nuvectis, Verastem, EQRX, GSK, ImmunoGen, Lilly, Zentalis, Roche/Genentech, Caris, Vincerx, NGM Bio. MF, NW, DP, AF: none to report.